DESCRIPTION: (Applicant's Abstract) The development of new synthetic methods and reactions to synthesize drug candidates and other organic molecules of importance in health-related research is a continuing goal of great importance. In the next granting period, cascade radical reactions will be developed in two different directions: 1) solid phase radical reactions will be developed with the aim of synthesizing moderate sized (100-200) libraries of antitumor and antiviral agents, and 2) new radical cascade sequences will be studied with the aim of preparing complex tri- and tetracyclic ring systems in one step from acyclic precursors. The specific aims are: 1) To develop an efficient and practical solid phase synthesis of the mappicine family of alkaloids based on our current solution phase cascade radical annulation of isonitriles. 2) To develop a new o-halobenzyl linker for attaching alcohols to the solid phase, and to release substrates from this linker to provide quantitative information about radical competition kinetics on the solid phase. 3) To synthesize a library of 100-200 individual pure analogs of mappicine and mappicine ketone antiviral agents using the knowledge gained in Aims 2 and 3. 4) To synthesize in solution (20 member) and on the solid phase (100 member) libraries of E-ring expanded analogs of the antitumor agent camptothecin. These compounds will be assayed for their lactone stability and their ability to kill cancer cells. 5) To develop a short synthesis of the tricyclic natural product gymnomitrene starting from a readily available acyclic precursor through a triple cyclization in the "round trip" radical class. 6) To complete sequence of competent model studies that will light the way to a round trip radical cyclization approach to one of the crinipellin class of antibacterial agents. 7) To complete a concise total synthesis of one of the crinipellins in enantiomerically pure form by using a round trip radical reaction that forms the complete carbon skeleton and all four rings in a single step from a readily available acyclic precursor.